Identification of biomarkers of lupus nephritis by systems biology approach

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which is important in Thailand. Inflammation and tissue damage occurs at many organs of SLE patients. Lupus Nephritis (LN) is a major complication of SLE that cause inflammation of the kidney. The mechanisms underlying SLE pathogenesis including genetics and environmental factors. The integrative systems biology approach by transcriptome and proteomic data were used in this study to identify new biomarker. Asian Lupus Consortium has reported some important SLE-related genes which are unique in Asian population. Furthermore, our recent result from Meta analysis combining with GWAS data has identified SLE-related genes in Asian SLE patients which are involved in demethylation processes. This confirms that the dynamics of DNA methylation level is a mechanism related with SLE pathogenesis. Therefore, the environmental factors including UV light, drugs or some kind of food may contribute to SLE pathogenesis through the DNA methylation dynamics. Understanding of this mechanism is important for improving SLE treatment because DNA methylation can be easier manipulated than the genes themselves. Most DNA methylation researches have focused on the promoter which controls gene expression; however, the repetitive sequences in genome are also controlled by DNA methylation are very interesting in SLE. We recently reported the DNA methylation dynamics of intersperse repetitive sequences (IRS) in CD4+, CD8+ T lymphocytes, B lymphocytes and neutrophils. The results show that HERV (human Endogenous retrovius), a transposable element which occupies 8% of the genome, is hypomethylated in CD3+CD4+ T lymphocytes. Since HERV can transcribe into mRNA, retrotranspose in the genome, as well as control expression of the neighbor genes, we hypothesized that HERV hypomethylation in the SLE cells can alter expression of the neighbor genes by transcribing chimeric transcripts. We analyzed HERV distribution in human genome and constructed EnHERV, which is the database that allows researchers to search HERV in human genome based on their pattern or interested genes. EnHERV also provides enrichment analysis function which can identify specific HERV pattern in published expression data. EnHERV is available at http://sysbio.chula.ac.th/enherv. We also attempt to identify the chimeric transcripts using publish RNA-Seq data in SLE patients. We hypothesized that HERV-LTR can alter the expression of their neighbor genes by using their regulatory mechanism. We aimed to discover novel chimeric transcripts, which are important in SLE pathogenesis and can be used as biomarkers for predict the prognosis, develop drugs and improve the treatment of SLE.